Signalling by membrane immunoglobulin, T cell receptors, and MHC molecules regulate lymphocyte maturation and development. For example, crosslinking of membrane immunoglobulin by antigen or by anti-immunoglobulin antibodies inactivates immature B cells, eliminating many of the B cells capable of producing autoantibodies; whereas crosslinking of membrane immunoglobulin promotes activation of mature B cells for clonal expansion and antibody production against foreign antigens. Activation of protein kinase activity and growth arrest of B cells by crosslinking of membrane immunoglobulin has been reported (Gold et al. (1990) Nature 345: 810; Campbell and Sefton (1990) EMBO J. 9: 2125). Anti-membrane immunoglobulin antibodies have been reported to exert inhibitory effects on cell proliferation of immature B cells, possibly by inducing programmed cell death, referred to as apoptosis (Benhamou et al. (1990) Eur. J. Immunol. 20: 1405). Apoptosis of cytotoxic T lymphocyte clones incubated in the presence of their specific epitopes but not in the presence of irrelevant epitopes has also been reported (Moss et al. (1991) J. Exp. Med. 173: 681). Recently, crosslinking of the APO-1 cell surface antigen which is expressed on the surface of activated human T and B lymphocytes has been reported to result in programmed cell death (Oehm et al. (1992) J. Biol. Chem. 267: 10709). The PD-1 gene, which is reportedly a member of the immunoglobulin gene superfamily, has been reported to be induced during programmed cell death of both a murine T cell hybridoma and a murine hematopoietic progenitor cell line (Ishida et al. (1992) EMBO J. 11: 3887).
Despite these reported findings, rational treatment methods for lymphoproliferative diseases, such as lymphomas and lymphocytic leukemias, are lacking. Currently, conventional combination chemotherapy remains the principal treatment of choice for these disease states. The efficacy of chemotherapy is limited, especially when patients fail first line drug regimens. Other therapy modalities need to be developed to overcome the limitations of chemotherapy. Anti-idiotype antibodies directed against cell surface immunoglobulins of individual lymphocytic neoplasms requires a lengthy and costly process to generate specific anti-idiotype antibodies for each patient individually, as each individual neoplasm likely has a unique idiotype. Moreover, development of anti-idiotype immunoglobulins depends primarily on immunization of nonhuman hosts, such as mice, which yields nonhuman immunoglobulins that are typically immunogenic when administered to humans. The necessity of humanization for therapeutic use of such antibodies would add to the cost and time expenditure, delaying treatment and making individualized anti-idiotype antibody therapy prohibitively expensive. Thus, although anti-idiotype antibodies might theoretically be potential tools for diagnosis and therapy of B cell lymphomas, practical considerations preclude their widespread use in medicine.
Thus there exists a need in the art for methods and compositions for diagnosis and therapy of lymphoproliferative diseases and other diseases of abnormal cell proliferation, including lymphomas and lymphocytic leukemias. It is one object of the invention to provide methods and compositions for diagnosing and treating these pathological conditions, as well as treating immunological conditions which are amenable to targeted anti-proliferative therapy. The present invention fulfills these and other needs.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.